Ferata drops and preparation method thereof

Abstract

The invention relates to the field of furalan preparations, in particular to furalan drops. According to the preparation method disclosed by the invention, by adding the cellulose ether and adjusting the ratio of the solvent, the furalan drop with good film forming property, adhesiveness and relatively low volatile performance is provided, so that the drop has better adhesiveness on the surface of animal skin, and meanwhile, the irritation of the drop to the surface of the animal skin is reduced; and the medicine can be better absorbed by animals.

Description

Technical Field

[0001] This application relates to the field of fluralaner preparations, and particularly to a fluralaner drop. Background Art

[0002] Fluralaner is a new type of isoxazoline insecticide. By blocking the γ-aminobutyric acid-gated chloride channel, it causes the insect nervous system to be overexcited and die, and can effectively control agricultural pests and pet parasites.

[0003] Fluralaner drops are a preparation developed using fluralaner, which are mainly used as an external antiparasitic preparation for pets such as cats and dogs. The most widely used product currently is Bravecto developed by Merck Sharp & Dohme, which currently occupies most of the market share. The main principle of the drops is to dissolve the drug and then penetrate through the animal's skin into the animal's body, and diffuse throughout the animal's body through the blood, thereby achieving the effect of systemic drug administration.

[0004] Since fluralaner drops are insoluble in water, partial organic solvents (such as dimethylacetamide) are usually used as solvents, and penetration enhancers are used in combination. However, during use, materials such as dimethylacetamide may have a strong stimulating effect on the animal's skin, and at the same time, due to its strong fluidity, its adhesion performance on the skin surface is also poor. Summary of the Invention

[0005] Based on the above technical problems, the purpose of this application is to improve its adhesion on the skin and reduce its stimulating effect on the animal epidermis by adjusting the formula on the basis of the existing fluralaner drops.

[0006] First, this application provides a fluralaner drop, which contains the following components by mass percentage:

[0007] Fluralaner, 20 - 30%

[0008] Penetration enhancer, 10 - 25%

[0009] Repellent, 5 - 20%

[0010] Cellulose ether, 2 - 10%

[0011] Organic solvent is supplemented to 100%;

[0012] The organic solvent is optionally any number of amide solvents, alcohol solvents or ketone solvents.

[0013] In the above solution, on the basis of the existing fluralaner drops, a small amount of cellulose ether is additionally added to the system. On the one hand, it can adjust the overall adhesion. The cellulose ether can improve the surface activity of the liquid in the system, so that the drops can better adhere to the animal body surface. At the same time, the cellulose ether can also adjust the overall volatility performance in the system, control its evaporation rate at a lower level, and improve its permeability on the body surface through long-term adhesion ability. At the same time, adding cellulose ether to the system can also reduce the irritation of the above drops, reduce its irritation to the animal body surface, and thus reduce the impact on the animal caused by the licking of the animal, resulting in the swallowing of the solvent.

[0014] Preferably, the organic solvent contains at least a combination of dimethylacetamide and acetone, and the mass ratio of dimethylacetamide to acetone is 1.5 - 5:1. Further preferably, the mass ratio of dimethylacetamide to acetone is 2.4 - 4:1.

[0015] In the above solution, it better balances low irritation and high film-forming property as a whole. The overall drops perform better on the body surface, enabling the drug to be better absorbed by the animal. Generally speaking, in the above solution, acetone of relatively low quality is selected, which has relatively low toxicity and irritation as a whole. Dimethylacetamide itself has low irritation and relatively slow evaporation as a whole, enabling fluralaner to better adhere to the animal body surface and enabling the body surface to better absorb fluralaner when wet.

[0016] Preferably, the mass of the cellulose ether is 30 - 50% of the mass of acetone.

[0017] In the above solution system, the cellulose ether mainly plays a role in wrapping and stabilizing acetone as a whole. Its addition amount is related to the mass of acetone. On this basis, it ensures good solubility and certain volatility, while also ensuring reduced irritation and increased adhesion.

[0018] Preferably, the cellulose ether is a non-ionic cellulose ether.

[0019] The non-ionic cellulose ether has better affinity with the skin on the one hand, produces less irritation as a whole, and has a better homogenizing effect on the system at the same time.

[0020] Preferably, it further includes polyvinylpyrrolidone. The molecular weight model of the polyvinylpyrrolidone is preferably not higher than K15. Further preferably, the addition amount of the polyvinylpyrrolidone is 1.5 - 3% by mass percentage.

[0021] Polyvinylpyrrolidone can further improve the adhesion and film-forming property in the above system. Meanwhile, it can further enhance the adhesion of the above drops on the body surface, reduce the flow, and improve the absorption performance. Among them, the polyvinylpyrrolidone model is preferably K12 or K15. Excessively high molecular weight polyvinylpyrrolidone or excessive addition amount will lead to too high viscosity of the system, difficult flow, and easy adhesion to the animal's hair, thus resulting in poor usability.

[0022] In this application, it also includes the preparation method of the above-mentioned fluralaner drops, which comprises the following steps: mixing each raw material component, fully stirring and mixing evenly, then filtering to remove impurities, and packaging. Preferably, in the mixing step, the stirring rate is 100 - 500 rpm, and the stirring time is 5 - 30 min.

[0023] In summary, this application provides a kind of fluralaner drops with good moldability, adhesion and low volatility performance, which makes the drops have better adhesion on the animal skin surface, while reducing the irritation to the animal skin surface, so that the drug can be better absorbed by the animal. Specific embodiments

[0024] The solutions in this application are further elaborated through the following specific embodiments.

[0025] For the fluralaner drops in this application, the following method is used to determine its effects:

[0026] 1. Adhesion: Use fresh pigskin to simulate the animal skin surface. After depilation, drop 1 mL of the drops on the pigskin surface, and then tilt the pigskin to measure the slipping angle when the drops drip at room temperature.

[0027] 2. Irritation: On the basis that the slipping angle meets not less than 45°, prepare a drops preparation without fluralaner, and determine its irritation through the back of the volunteer's hand, and score it according to 0 points (no irritation, reference ethanol) - 10 points (with a stinging sensation). It should be noted that this index is mainly used to evaluate the discomfort of the preparation to the skin surface.

[0028] 3. Stability: Place the prepared drops at room temperature and observe whether there is stratification and precipitation after 6 months.

[0029] 4. Irritation: Select some embodiments to conduct experiments by administering drugs to healthy dogs. The dosage is 0.2 mL / kg, and the drug is administered once a day. Observe whether there is any skin irritation phenomenon in the animals during this period.

[0030] 5. Fluidity: Observe whether the drug can smoothly penetrate through the hair layer and contact the skin surface during the drug administration process, and record it as poor, medium, and good according to fully adhering to the hair, mostly adhering to the hair, and slightly adhering to the hair respectively.

[0031] In the following embodiments, the preparation method of the drops is as follows:

[0032] S1. Preparation: First, weigh each raw material and add it to the liquid preparation tank, then add fluralaner, and stir at a speed of 200 rpm for 10 min;

[0033] S2. Filtration: Filter the prepared liquid medicine through a microporous filter membrane with a pore size of 0.45 μm.

[0034] S3. Sealing: Fill the filtered liquid medicine into aluminum-plastic tubes according to the weight of each specification, and then seal the tails of the aluminum-plastic tubes. The sealing temperature is 170°C to 250°C. The reticulation at the sealed tail is clear, the sealing performance is good, and there is no phenomenon of leakage.

[0035] Example 1. In this example, the effects of adding different types and qualities of cellulose ethers on adhesion, irritation, stability, and fluidity were mainly studied under the formula of a fixed solvent. Specifically, in this example, except for cellulose ether, the overall material configuration table is shown in Table 1.

[0036] Table 1

[0037] Material Mass percentage Furalaner 25％ Tetrahydrofuran polyethylene glycol ether (penetrant) 16％ Diethyltoluamide (repellent) 12％ Polyvinylpyrrolidone K15 2％ Organic solvent Make up to 100%

[0038] Among them, the organic solvent is dimethylacetamide and acetone with a mass ratio of 3:1.

[0039] For this example, the specific experimental results are shown in Table 2.

[0040] Table 2

[0041]

[0042]

[0043] In the above table, the control example is a commercially available preparation. By comparison, it can be seen that the solution in this application significantly improves the sliding angle on the skin surface compared with the commercially available mature product, significantly improves its adhesion, and helps it to remain attached to the pet's body surface for a long time.

[0044] Based on the above experimental data, all three cellulose ethers can achieve the effect of surface activity. The sliding angle on the skin surface will increase with the increase in the addition amount of cellulose ether and remain stable overall after exceeding 10%. At the same time, the relationship between the irritation to the skin and the addition of cellulose ether is relatively small. Overall, the irritation of carboxymethyl cellulose ether to the skin is stronger than that of methyl cellulose ether and hydroxypropyl methyl cellulose ether. In another case, too high a concentration of cellulose ether will have an adverse effect on the system. The breaking and polymerization of its molecular chains easily lead to a certain amount of precipitation in the system and also have a certain adverse effect on fluidity.

[0045] Example 2. In this example, on the basis of selecting methyl cellulose ether, the mass percentages of acetone, dimethylacetamide, and hydroxypropyl methyl cellulose in the solvent were further adjusted, and the results are shown in Table 3.

[0046] Table 3

[0047]

[0048] Combining the examples of Example 1 and Example 2, it can be seen that when the mass of the cellulose ether is 30-50% of the mass of acetone, the system can have better adhesion performance, and it has a higher slip angle as a whole. When the addition amount of the cellulose ether is lower, there will be an obvious phenomenon of enhanced irritation in the system. The selection of the solvent has an obvious impact on the fluidity and irritation of the system. The increase in acetone will significantly increase the irritation on the body surface, while dimethylacetamide will cause a certain increase in the viscosity of the system. In addition, when the content of acetone is too high, the system is prone to stratification and also prone to produce a certain amount of precipitation, which may be caused by the poor solubility of acetone.

[0049] Example 3. In this example, the effects of the addition and types of polyvinylpyrrolidone on the overall performance of the system were mainly studied. In this example, based on Examples 1-9, polyvinylpyrrolidone K12, polyvinylpyrrolidone K15, and polyvinylpyrrolidone K17 were selected, and the specific experimental results are shown in Table 4. In Table 4, the increase or decrease in the mass of polyvinylpyrrolidone was made up by organic solvents.

[0050] Table 4

[0051]

[0052] It is not difficult to see from the above experiments that with the increase in polyvinylpyrrolidone and the increase in the molecular weight of polyvinylpyrrolidone, it will have an obvious effect of reducing fluidity. After using polyvinylpyrrolidone with a label higher than K17, it has been difficult to ensure both its adhesion to the skin surface and good fluidity at the same time.

[0053] Example 4. Select experimental groups 1-9 for animal experiments and compare them with commercially available preparations. The above preparations were dropped on the skin between the shoulders and the buttocks of the dog's back. For each 1 kg of body weight, the dog was given ≥25 mg, with the specific mass shown in Table 6, and administered once every 12 weeks.

[0054] Before use, open the small bag, take out the dropper, avoid direct contact with this product, hold the bottom of the dropper or the fixed part below the upper end cap, keep the top of the dropper facing up, and rotate the end cap clockwise or counterclockwise for one full turn. When the sealing ring breaks, the dropper is opened, and the dropper cap should be retained on the dropper and cannot be removed.

[0055] Table 5 Administration schedule for test dogs

[0056]

[0057] Table 6 Administration doses for test dogs

[0058]

[0059] Before drug administration (D0), D2, D28, D56, D70, and D84, count the number of ticks on the whole body surface of the test dogs, and calculate the tick reduction rate at different time points after drug administration for each animal. At the same time, conduct a clinical general examination, measure body temperature (rectal temperature), respiratory rate, and heart rate, check for local body surface itching, skin damage, red rashes, etc. caused by tick bites, and perform a skin lesion degree score. Observe the mental state, appetite, and defecation situation every day during the test, and record various adverse reactions that occur.

[0060] In this test, the average tick reduction rate of each group of test dogs is used as the main efficacy index. Specifically, for the main efficacy index, refer to Note 1 of the "Guidelines for the Testing and Evaluation of the Efficacy of Antiparasitic Substances in the Treatment and Prevention of Tick and Flea Infections in Dogs and Cats" issued by the EMA in 2022, and calculate the average tick reduction rate on the body surface of the two groups of test dogs at D2, D28, D56, D70, and D84:

[0061]

[0062] Evaluation criteria for the results of the clinical pharmacodynamic tests of each group:

[0063] Effective: During and after drug treatment, the average tick reduction rate on the body surface ≥ 90%, and there is no itching, no red rashes, no dandruff, or damage caused by the test animal's self-biting at the affected part.

[0064] Ineffective: During and after drug treatment, the average tick reduction rate on the body surface < 90%, and there is still obvious itching, red rashes, dandruff, or self-biting damage of the test animal at the affected part.

[0065] For each group of experimental dogs, the results of the efficacy experiments are shown in Tables 7 - 9. Among them, Table 7 shows the overall experimental results for various types of ticks, and Tables 8 and 9 show the experimental results of the above drugs against *Rhipicephalus sanguineus* and *Haemaphysalis longicornis*, respectively.

[0066] Table 7 Statistical results of tick counts for each group of test dogs (pcs)

[0067]

[0068] Table 8 Statistical results of tick counts for each group of test dogs infected with *Rhipicephalus sanguineus* (pcs)

[0069]

[0070] Statistical results of tick counts of experimental dogs infected with *Haemaphysalis longicornis* in each group (pcs)

[0071]

[0072] 48 h after drug administration (D2), 78.13% (50 / 64) and 83.08% (54 / 65) of the ticks on the experimental dogs in Group Ⅰ and Group Ⅱ died completely. Most of the dead ticks fell off the skin automatically, and shriveled and dull tick corpses could be seen on the ground. In addition, tick corpses could also be found among the dog's hair. Most of the remaining ticks on the experimental dogs were also poisoned to death, and some of the surviving ticks showed decreased vitality. After calculation, the average tick reduction rates of the experimental dogs in Group Ⅰ and Group Ⅱ at D2 were 94.10% and 94.78% respectively, reaching the effective standard (90%). Further analysis of the average reduction rates of each tick species found that the average reduction rates of *Rhipicephalus sanguineus* in Group Ⅰ and Group Ⅱ were 94.90% and 95.44% respectively; the average reduction rates of *Haemaphysalis longicornis* were 93.54% and 94.34% respectively, reaching the effective standard (90%).

[0073] On the 28th day after drug administration (D28), the ticks on the experimental dogs in Group Ⅰ and Group Ⅱ had basically all died and fallen off, and tick corpses were occasionally visible among the hair. Only 7.81% (5 / 64) and 6.15% (4 / 65) of the experimental dogs in Group Ⅰ and Group Ⅱ had a small number of live ticks. After calculation, the average tick reduction rates of the two groups of experimental dogs were 99.75% and 99.77% respectively, both reaching the effective standard (90%); the efficacy of tick control in Group Ⅰ and Group Ⅱ decreased at D56, D70 and D84 after drug administration, but remained above the effective standard (90%). Further analysis showed that at D28, D56, D70 and D84, the average reduction rates of *Rhipicephalus sanguineus* and *Haemaphysalis longicornis* in Group Ⅰ and Group Ⅱ were also above the effective standard.

[0074] Based on the above results, the average tick reduction rates of Group Ⅰ and Group Ⅱ reached the 90% effective standard at D2 and remained until D84.

[0075] It was found through between-group comparison that there was no significant difference in tick counts between Group I and Group II at different time points overall (P = 0.971 > 0.05). Since there was no interaction between group and time (P = 0.94 > 0.05), no further analysis was conducted for each group at each time point. Further analysis and comparison of the results for each tick species showed that there was no significant difference in the counts of Rhipicephalus sanguineus between Group I and Group II at different time points overall (P = 0.696 > 0.05). Since there was no interaction between group and time (P = 0.340 > 0.05), no further analysis was conducted for each group at each time point; there was no significant difference in the counts of Haemaphysalis longicornis between Group I and Group II at different time points overall (P = 0.703 > 0.05). Since there was no interaction between group and time (P = 0.841 > 0.05), no further analysis was conducted for each group at each time point.

[0076] This specific embodiment is only an interpretation of the present application and does not limit the present application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A Frellana drops, characterized in that The components are as follows according to mass percentage: Frellana, 20-30% Penetrant, 10-25% Repellent, 5-20% Cellulose ether, 2-10% The organic solvent is replenished to 100%; The organic solvent may be any number of amide solvents, alcohol solvents or ketone solvents.

2. A Frellana drops and a preparation method thereof according to claim 1, characterized in that: The organic solvent at least comprises a combination of dimethylacetamide and acetone, and the mass ratio of dimethylacetamide to acetone is 1.5 to 5:

1.

3. A Freylana drops according to claim 2, characterized in that, The mass ratio of dimethylacetamide to acetone is 2.4-4:

1.

4. A Frellana drops according to claim 3, characterized in that: The mass of the cellulose ether is 30-50% of the mass of acetone.

5. A Frellana drops according to claim 1, characterized in that: The cellulose ether is nonionic cellulose ether.

6. A Frellana drops according to claim 1, characterized in that: Also included are polyvinylpyrrolidone.

7. A Frellana drops according to claim 5, characterized in that: The molecular weight model of the polyvinyl pyrrolidone is not higher than K15.

8. A Frellana drops according to claim 5, characterized in that: The added amount of the polyvinyl pyrrolidone is 1.5-3% by mass.

9. The method for preparing the Frellana drops according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: mixing the raw material components, stirring them fully and mixing them evenly, filtering and removing impurities, and packaging.

10. The method for preparing Frellana drops according to claim 8, characterized in that: In the mixing step, the stirring rate is 100 to 500 rpm, and the stirring time is 5 to 30 minutes.

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